Building an Accurate Chromosome Segregation Machine in Fission Yeast

Abstract

In fission yeast, erroneous attachments of spindle microtubules to kinetochores are frequent in early mitosis. Most are corrected before anaphase onset by a mechanism involving the protein kinase Aurora B which destabilizes kinetochore microtubules (ktMT) in the absence of tension between sister chromatids. We previously described a minimal mathematical model of fission yeast chromosome segregation based on the stochastic attachment and detachment of kinetochore microtubules. This model accurately reproduces the timing of correct chromosome bi-orientation and segregation seen in fission yeast. This force-balance model of mitosis describes global spindle dynamics and predicts chromosome segregation defects (Courtheoux J.Cell Biol 2009; Gay, J.Cell Biol 2012).We recently implemented new features to our model that describe kinetochore alignment during metaphase. In higher eukaryotes, efficient chromosome congression relies, among other players, on the activity of chromokinesins. We provide a quantitative analysis of kinetochore oscillations and positioning in S. pombe, a model lacking chromokinesins. In wild type cells, chromosomes align during prophase and while oscillating, maintain this alignment throughout metaphase. Chromosome oscillations are dispensable both for kinetochore congression and stable kinetochore alignment during metaphase. We propose that Kinesin-8 aligns chromosomes by controlling pulling forces in a length dependent manner. Our chromosome segregation model implemented with a length-dependent process that controls the force at kinetochores is sufficient to mimic congression and to prevent aneuploidy. These model illustrate how a motor protein at kinetochores provides spatial cues within the spindle to align chromosomes.Altogether, our work illustrates how a simplified force balance model, with stochastic attachment and detachment events, correction mechanisms (Aurora B, and kinetochore orientation effect) and a length dependent process for kinetochore alignment, can explain the segregation of chromosomes with a timing and accuracy similar to chromosome segregation in living wild-type fission yeast cells.